19-nor-delta1(10)-5alpha-pregnen-17alpha-ol-2, 20-dione and derivatives thereof



United States Patent phenanthrene derivatives and to a process for theproduc- 10 tion thereof.

More particularly, the present invention relates to novel 19-nor-A-5a-pregnen-17a-ol-2,20-dione derivatives, to the 6a-methyl, and/or 1600or 16B-methyl derivatives thereof, as well as to the correspondingllfl-hydroxy or 15 ll-keto and or 2l-hydroxy derivatives thereof, andfurther, to the respective C-17 and or C-21-esters.

The novel compounds of the present invention are represented by thefollowing formulae:

on, om-on 20 i H2 I In the above formulae R and R each, representshydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbonatoms; R represents hydrogen, d-mtithyl or ,E-methyl; R representshydrogen or methyl and X represents hydrogen, a keto-group or aB-hydroxylgroup.

The acyl groups are derived from hydrocarbon carboxylic acids containingless than 12 carbon atoms which may be saturated or unsaturated, ofstraight, branched, cyclic or cyclic-aliphatic chain, or aromatic, andmay be substituted by functional groups such as hydroxy, alkoxy,containing up to 5 carbon atoms, acyloxy containing up to 12 carbonatoms, nitro, amino or halogen. Typical ester groups are the acetate,propionate, enanthate, benzoate, trimethylacetate, t-butylacetate,phenoxyacetate, cyclopentylpropionate, aminoacetate, and,B-chloropropionate.

The compounds represented by Formula A are progestational compounds withoral activity, useful in the control of fertility and they also exhibitanti-estrogenic and anti-gonadotrophic activities. In addition theylower the blood and adrenal cholesterol levels.

The compounds represented by Formula B have antiinflammatory propertiesand glycogen cumulative activities. In addition they reduce the thymusand are antiestrogenic and anti-gonadotrophic hormones.

The novel compounds of this invention are prepared by the processexemplified by the following equation:

OCH OCH3 1C H1C 0- O O-CO I CHg I CHg NwRl .wvRl

5 j I I R 0 I R50 I H i H R a OCH l OCIIg 1110 w H2O I o- -o o-c-o CH: IMR1 MR1 H 3 I I l I no IV I III E l R s O-CH O-CH; mo 1120 I o- -o o-o-oI on, I H, (\I NWRX NWR! H i] no i O: l I i v i W H r H O: l l i VIII iv11 H I H i GH --01} CH; 43:0 =0 l..... I..... Y lwvRl AAN R1 0 O:

P IX E X H l H l In the above formulae R, R R and R have the samemeaning as previously set forth; R represents hydrogen, a lower alkylradical of less than 8 carbon atoms or a hydrocarbon carboxylic acylgroup of less than 12 carbon atoms; R represents hydrogen or a loweralkyl radical of less than 8 carbon atoms and Y represents ,B-hydroxy orketo.

In carrying out the, above outlined process, the starting compound (I)which is a 17,20;20,2l-bismethylenedioxy- 19-nor-A -pregnatrien 3 o1derivative, the corresponding lower alkyl-3-ether described in US.Patent No. 3,002,968 or the 3-acyl derivative thereof (prepared byconventional esterification of the respective 3-free hydroxyl compound,preferably by treatment with an anhydride derived from a hydrocarboncarboxylic acid of less than 12 carbon atoms and in the presence ofp-toluenesulfonic acid) is hydrogenated in the presence of a catalyst,such as ruthenium dioxide preferably in an ethanolic suspension andunder a pressure varying between 80 and 200 atmospheres, generally at atemperature which varies from ambient temperature to 150 C. to producethe 17,20;20,2l-bismethylenedioxy 19 nor-5a,l0a-pregnan- 35-01 or thecorresponding 3-alkyl ether thereof (II). This 3B-hydroxy steroidcompound upon reaction with acetic anhydride and boron trifluorideetherate in the presence of an alkali metal halide, such as lithiumhalide and at steam bath temperature, gives the corresponding17,20;20,2l-bismethylenedioxy 19 nor-5a,10a-A -pregnene derivative(III). Treatment of this compound with diborane, dissolved in a suitablesolvent such as tetrahydrofuran, followed by reaction of the organoboronsteroid compound thus formed with hydrogen peroxide in the presence ofan aqueous solution of sodium hydroxide and at a temperature of around15-30 0, produces the17,20;20,2l-bismethylenedioxy-19-nor-5a,10ot-pregnan-2ot- 01 (V) as wellas the corresponding17,20;20,21-bismethylenedioxy-19-nor-5a,l0a-pregnan-3fi-ol (IV) whichmay be easily separated by column chromatography or by fractionalcrystallization. Upon oxidation of the 17,20;20,2l-bismethylenedioxy 19I1OI-50t,100-PICgI12tI1 21-01 (V) by conventional methods, such as forexample treatment with an 8 N solution of chromium trioxide inacetone-sulfuric acid solution (Jones reagent) and at a temperaturepreferably around 0-5 C., produces 17,20;20,2l-bismethylenedioxy 19nor-5a,10a-pregnan- 2-one (VI). Upon introduction of a double bond intothe latter compound, between 0-1 and C-10 positions, preferably byreaction of the aforesaid saturated ketone (VI) with 1.1 molarequivalents of bromine in acetic acid and in the presence of hydrobromicacid and the subsequent dehydrohalogenation of the thus obtained 1-bromo-Z-keto-steroid compound, principally by heating under reflux withcalcium carbonate in a nitrogenated organic solvent, such asN-dimethylformamide, there is produced 17,20;20,21-bismethylenedioxy-19nor-A -5a pregnen-Z-one (VII). The 17,20;20,2l-bismethylenedioxygrouping of the latter compound is conventionally hydrolyzed with anacid such as formic acid to produce the corresponding17u,21-dihydroxy-20-keto compounds (VIII; R and R =H). The conventionaltreatment of these steroid derivatives, preferably with an anhydridederived from a hydrocarbon carboxylic acid of less than 12 carbon atomsand in the presence of pyridine produces the respective C-21 acylates of19-nor-A -5a-pregnene- 17a,21-diol-2,20-dione (VIII; R=H; R =acyl). Theconventional esterification of the free hydroxyl group at C-17a of thelast mentioned compounds, with a hydrocarbon carboxylic anhydride of thetype described above (which hydrocarbon chain may be equal or differentto the one of the acyl radical previously attached to C-21) and in thepresence of p-toluenesulfonic acid, produces the C-l7, C-21-diacylatesof 19-nor-A -5a-pregnene- 17oc,21-di0l2,20-di01'l6 (VIII; R and R=acyl).

The compounds derived from 21-monoacylate of 19- nor-A-5a-pregnene-17a,21 diol 2,20 dione (VIII; R=H; R =acyl) upon incubationwith adrenal glands in a suitable medium, for example an aqueoussolution of alkali metal phosphate and chlorides and magnesium sulfate,mixed with an aqueous solution of fumaric acid and sodium hydroxide fora period of time of the order of 3 hours, approximately at a temperatureof around 28-37 C. produced the corresponding 21-acylate of 19- norA100) oz pregnene-ll,8,l7a, 2l-triol-2,20-dione (IX: R =acylgY=B-hydroxy) which upon subsequent oxidation, preferably with 8 Nsolution of chromium trioxide in acetone-sulfuric acid solution (I onesreagent), produce the corresponding 19-nor-A 5a pregnene- 17a,21 diol2,11,20-trione 21-acylate derivatives (IX; R acyl; Y=keto).

The elimination of the Zl-hydroxy group of the 19- nor-A-5a-pregnene-l7a,2l-diol-2,20-dione derivatives (VIII: R and R =H) iscarried out by treatment with tosyl chloride in pyridine solution andsubsequent detosylation of the formed 2l-tosylate, as per heating underreflux with sodium iodide in acetic acid, to give the respective19-nor-A -5a-pregnen 17cc ol-2,2O dione (X; R=H). Conventional acylationof this compound with an acylating agent such as anhydride of ahydrocarbon carboxylic acid of the previously defined type and in thepresence of p-toluenesulfonic acid produces the 17-acylates of theaforesaid compound (X; R=acyl).

The following specific examples serve to illustrate the presentinvention but are not intended to limit it:

PREPARATION 1 To a solution of grams of 6ot,l6;3-dimethyl-Apregnadiene-17eg21-diol-3,20-dione in 400 cc. of chloroform, were added80 cc. of a 37% aqueous solution of formaldehyde and 10 cc. ofconcentrated hydrochloric acid and the mixture was stirred during 48hours at room temperature. The two layers were separated, the aqueouslayer was washed with chloroform, and the organic solution combined andWashed to neutral with water, dried over anhydrous sodium sulfate andevaporated to dryness. The residue was recrystallized from methanolether thus producing 6a,16B-dimethy1 17,20;20,21 bismethylenedioxy-A-pregnadien-3-one.

A solution of 7 g. of 6oz,16/8-dirnethy117,20;20,2l-bismethylenedioxy-A-pregnadien-3-one in 400 cc. of mineral oil was added dropwise,approximately 2 cc. per second, through a glass tube (32 x 3.0 cm.)filled with Pyrex glass helices and heated to 600 C. The resultingcloudy dark yellow solution was passed though a column containing 300 g.of ethyl acetate-washed alumina and the mineral oil was washed out withhexane. Elution with hexane-benzene and benzene gave the startingmaterial, whereas further elution with benzene-ether and ether furnishedsemisolid fractions. These on crystallization from acetone-hexane,followed by recrystallization of the solid product from acetone, gave6a,16,8 dimethyl- 17,20;20,2l bismethylenedioxy-l9-nor-A-pregnatrien-3-ol.

To a solution of 5 g. of preceding compound in 100 cc. of anhydrousbenzene were added 1 g. of p-toluenesulfonic acid and cc. of aceticanhydride and the mixture was allowed to stand for 24 hours at roomtemperature, poured into ice water and the resulting mixture stirred toeffect hydrolysis of the excess anhydride. The benzene layer wasseparated and washed with 10% sodium carbonate solution and water.Drying, evaporation and crystallization of the residue from ether-hexaneproduced the acetate of6a,16,8-dimethyl-17,20;20,2l-bismethylenedioxy-l9-nQr-A-pregnatrien-3-ol.

lGB-methyl-A -pregnadiene-l7a,2l-diol 3,20 dione was treated followingthe same reaction sequence, thus producing consecutively16fi-methyl-17,20;20,21-bismethylenedioxy-A-pregnadien-3-one,16,B-methyl-17,20;20,21- bismethylenedioxy-19-nor-A-pregnatrien-3 01 and finally the corresponding acetate thereof.

PREPARATION 2 The starting compounds listed under I were treatedfollowing the same esterification procedure as described in Preparation1, except that acetic anhydride was substituted by propionic anhydride,to give the respective esters listed under II:

Starting Compounds Esters I II 60:, l6,8-dimethyl-17,2020,21-

bisrnethylenedioxy-lQ-non A -pregnatrien-3-0l.l6fl-methyl-17,20;20,21-bisn1ethylenedioxy-lt -norn 3 -pregnatrien-3-0l.17,20;20,2l-bisrnethylene dioxy-lQ- nor-A -pregnatrlen-3-01.

Example I A solution of 50 g. of the 3-rnethyl ether of 6a,16ocdirnethyl17,20;20,21 bismethylenedioxy 19 nor- A -pregnatrien-3-ol (U.S. PatentNo. 3,002,968) in 700 cc. of ethanol was hydrogenated firstly in thepresence of 1.2 grams of ruthenium dioxide catalyst (RuO under apressure of 1,600 psi. and at room temperature; then the mixture washeated to C. The hydrogenation was continued during 7 hours. The mixturewas cooled, the catalyst filtered off and the filtrate evaporated todryness. By chromatography of the residue through aneutral aluminacolumn and recrystallization of the solid fractions eluted with benzeneether (60:40) there was obtained the 3-methy1 ether of6a,16a-dimethyl-17,20;20,2lbisrnethylenedioxy-19-nor-5ot,10rt-pregnan-3Bol (Cornpound No. 1).

The starting compounds listed under I were treated by the same procedureto produce the corresponding products under II.

I Cpd. II No.

6a,16B-dlmethyl-17,20;20-21- 2 6a, 1618-dimethyl-17,20;20-21-brsmethylenedioxy-lQ-norblsmethylenedioxy-lQ-nor- A -pregnatrien-Zl-ol.5a,10a-pregnan-3fl-ol.

16fl-methyl-17,20;20,21-bismethylenedioxy-19-n0r-5a, IOa-preguan-ZiB-ol.

6:1,16B-dlmethy1-17,20;20,21-

bismethylenedloxy-IQ-nor- 5a,10a-pregnan-35-ol.

3,6 17,20;20,21-bismcthylenedioxygarter-A M -pregnatrien-19-nor-5a,10a-pregnan-3B-ol.

16a-methy1-17,20;20-21-bis- 516iz-methyl-17,20;20,21-bismethylenedioxy-Ql-normethylenedl0xy-19-nor-5a,A 3 -pre gnatrlen-3-ol. 10a-pre gnan-Bfl-ol.

8-rnethyl ether of Ida-methyl 6 3-methyl ether of 16a,methyl-17,20;20,21-bismethylenedi- 17,20;20,21-blsmethylened1- 0xy-19-nor-A-pregnaoxy-l9-n0r-5a,10a-pregnantricn-3-ol. 3;3-01.

3-rnethyl ether of 17,20;20,21- 7 ii-methyl ether of 17,20;

bismethylenedioxy-lQ-nor- A M 00) -pregnatrien-3-ol.

3-methyl ether of fizz-methyl 8 17,20;20,21-bisrnethylenedi-17,20;20,2l-blsmethylenedloxy-19-nor-A -preg-0xy-19-nor-5a,mix-pregnannatrien-3-ol. 38-01.

20,21-bismethylene-dioxy- 19-n0r-5a-10a-prognan-36-ol. 3-methyl ether of(la-methyl- Example II A mixture of 10 g. of the 3amethyl ether of6,16a-dimethyl-17,20;20,2l-bismethylenedioxy-19 nor 512,100:- pregnan-38-ol (Cpd. No. 1), 50 g. of anhydrous lithium bromide, 250 cc. offreshly distilled acetic anhydride and 6 cc. of boron trifluorideetherate, also freshly distilled, was heated in a steam bath for 2hours. The mixture was poured into ice Water and was stirred until theexcess of anhydride was hydrolized, then extracted several times withethyl acetate in portions of 500 cc. each. The combined organic extractswere washed with sodium bicarbonate solution and then with water untilneutral. The organic solution was dried over sodium sulfate andevaporated to dryness, the product was crystallized from methanol togive 6a,16a-dirnethyl-17,20;20,21-bismethylenedioxy-19-nor-5a,IOa-A-pregnene (Cpd. No. 9).

Following exactly the same technique, there were treated the compoundsNos. 2 to 8, inclusive, thus producing respectively:

Cpd. No.2

10. 6a,16fl dimethyl 17,20;20,21 bisrnethylenedioxy-19-nor-5a,IOa-Apregnene.

11. 16B methyl 17,20;20,21 bismethylenedioxy- 19-nor-5a,10a-A -pregnene.

12. 17,20;20,21 bismethylenedioxy-l9-nor-5a,10a-

A tpregnene.

13. 16a methyl 17,20;20,21 bismethylenedioxy- 19-nor-5a,lOa-a -pregnene.

13. 16a-methyl-l7,20;20,2l'bismethylenedioxy 19- nor-a,10a-A -pregnene.

12. 17,20;20,2l-bismethylenedioxy-l9-nor 5a,10a-

A -pregnene.

14. 6oz methyl 17,20;20,21-bismethylenedioxy-19- nor-5a,10a-A -pregnene.

Example III A slow stream of diborane was passed through a solution ofg. of 6oz,1Got-dimethyl-17,20;20,2l-bismethylenedioxy-19-nor-5a,10a-A-pregnene (Cpd. No. 9) in 125 cc. of tetrahydrofuran for 1 hour. (After20 minutes the solution became warm and then the temperature slowlysubsided.) The excess of diborane was decomposed by careful addition ofwater. Then 1 it. of water was added and the formed precipitate wasfiltered, washed and dried, thus giving 9.6 g. of the organoboroncompound.

This material was dissolved in 200 cc. of tetrahydrofuran and treatedwith 9 g. of sodium hydroxide previously dissolved in cc. of water, andcc. of 35% hydrogen peroxide, stirring and keeping the temperaturearound 15 C. The mixture was stirred for 2 hours, after this time, theprecipitated product was filtered, Washed and dried. The total crudeproduct was chromatographed on a 300 g. neutral alumina column; theeluates obtained with a mixture of benzene-hexane (80:20) produced6a,16adimethyl-17,20;20,2l-bismethylenedioxy 19 nor-5a,10a-pregnen-3a-ol (Cpd. No. 15) and from the fractions eluted withbenzene-ether (80:20), there was obtained 6a,].6ocdimethyl-17,20;20,2l-bisrnethylenedioxy- 19-nor-5a,10a-pregnan-2a ol(Cpd. No. 16), the latter compound predominating in the isomers mixture.

The compounds Nos. 10, 11, 12, 13, and 14 were treated following thesame procedure thus producing respectively:

Cpd. No.:

17. 6a,16,8 dimethyl 17,20;20,21bismethylenedioxy-19-nor-5a,lOa-pregnan-Sa-Ol.

18. 165-me-thyl-17,20;20,2l-bismethylenedioxy 19-nor-5a,l0a-pregnan-3a-ol.

19. 17,20;20,21-bismethylenedioxy-19-nor :,10a-

pregnan-3 a-ol.

20. 16a-methyl-17,20;20,21 bismethylenedioxy 19-nor-5a,10a-pregnan-3a-ol.

21. 6a methyl 17,20;20,21-bismethylenedioxy-19-nor-5a,10a-pregnan-3a-ol.

together with the corresponding 2a-hydroxy isomers:

22. 6a,16,8 dimethyl 17,20;20,21 bismethylenedioxy 19 nor5a,10a-pregnan-2a-ol.

23. 16,6 methyl 17,20;2(),2l-bismethylenedioxy-lSnor-5a,lOa-pregnan-Za-ol.

24. l7,20;20,2l bismethylenedioxy 19-nor-5a,l0a-

pregnan-2a-ol.

Cpd. No.1

25. methyl 17,20;20,21 bismethylenedioxy- 19-nor-5a,10a-pregnan-2u-ol.26. 60c methyl 17,20;20,21 bismethylenediox 19-nor-5a,IOa-pregnan-Za-ol.

Example IV A solution of 1 g. of601,1Got-dimethyl-17,20;2O,21-bismethylenedioxy-19-nor-5a,10a-pregnen-2a-ol(Cpd. No. 16) in 10 cc. of acetone was cooled to 0 C, and treated underan atmosphere of nitrogen and with stirring, with a solution of 8 Nchromic acid (prepared by mixing 26 g. of chromium trioxide with 23 cc.of concentrated sulfuric acid and diluting with water to 100 cc.), untilthe color of the reagent persisted in the mixture. It was stirred for 5minutes further at 0-'5 C. and diluted with water. The precipitate wascollected, washed with water and dried under vacuum, thus affording acrude product which upon recrystallization from acetone-hexane gave6a,16a-dimethyl-17,20;20,2 l-bismethylenedioxy 19 nor-5a,10a-pregnan-2-one (Cpd. No. 27).

The 2a-hydroxy steroid compounds Nos. 22 to 26, inclusive, were treatedaccording to the preceding example to give respectively:

Cpd. No.:

28. 6a,16fl-dimethyl-l7,20;20,2l-bismethylenedioxy-19-nor-5a,10a-pregnan-2-one.

29. methyl-17,20;20,2l-bismethylenedioxy-l9- nor-5a,l0a-pregnan-2-one.

30. 17,20;20,21 bismethylenedioxy 19 HUI-5a,-

lOa-pregnan-Z-one.

31. 16a methyl 17,20;20,2l bismethylenedioxy-19-nor-5a,10a-pregnan-2-one.

32. 60c methyl 17,20 ;20,21 bismethylenedioxy-19-nor-5a,10a-pregnan-2-one.

Example V A solution of 5 g. of compound No. 27 (prepared according toExample IV) in 100 cc. of acetic acid was treated with a few drops ofhydrogen bromide in acetic acid and subsequently dropwise and withstirring, with a solution of 1.1 molar equivalents of bromine in 50 cc.of acetic acid. After all the bromine had been consumed, Water wasadded, the formed precipitate filtered, washed with water to neutral anddried under vacuum. Recrystallization from acetone-hexane yieldedl-br0m0-6oc,l6a-dimethyl-19-nor-5u,10a-pregnan-2-one.

2 g. of the preceding l-bromo-Z-keto steroid compound in 40 cc. of colddimethylformarnide Was added over 15 minutes to a suspension of 5 g. offinely divided calcium carbonate in 15 cc. of refluxingdimethylformamide. The mixture was refluxed for 30 minutes further,cooled and filtered. The filtrate was diluted with Water and extractedwith ethyl acetate. The extract was washed with dilute hydrochloricacid, water, aqueous sodium bicarbonate solution and water, then driedover anhydrous sodium sulfate and evaporated to dryness. Silica gelchromatography. and recrystallization afforded 6a,16a-dimethyl-17,20;20,21 bismethylenedioxy-19-nor-A 5a pregnen-Z-one (Cpd. No. 33).

The compounds Nos. 28 to 32, inclusive were treated following the sameprocedure, thus producing respectively:

Cpd. No.:

34. 6a,16fl dimethyl-17,20;20,2l bismethylenedioxy-19-nor-A-Sa-pregnen-Z-one.

35. 16,8 methyl 17,20;20,21-bismethylenedioxy-l9- nor-A--5a-pregnen-2-one.

36. 17,20;20,2l-bismethylenedioxy 19 nor-A 5a-pregnen-2-one.

37. 16a methyl-17,20;20,2l-bismethylenedioxy-19- nor-A-5a-pregnen-2-one.

38. 6a methyl 17,20;20,2l-bismethylenedioxy-19- nor-A -5a-pregnen-2-one.

9 Example VI 1 g. of 6a,16a-dimethyl-17,20;20,2l-bismethylenedioxy-19-nor-A -a-pregnen-2-one (Cpd. No. 33) was heated on the steam bathwith 20 cc. of 60% formic acid for 1 hour, cooled, diluted with waterand the precipitate was collected, washed with water, dried andrecrystallized from acetone-hexane, thus affording60,16uc-dlt116tl1Yl-l9- nor-A -Sa-pregnene-17a,21-diol-2,20-dione (Cpd.No. 39).

The compounds Nos. 34 to 38, inclusive, were reacted in the same mannerto give respectively:

Cpd. No.:

40. 6a,16B dimethyl 19 nor-A -5a-pregnene- 17a,21-diol-2,20-dione.

41. 16,8-methyl-l9-nor-A derregnanc-17a,-17a,-

21-diol-2,20-dione.

42. 19-nor-A -5a-pregnene-17a,21-diol-2,20-di0ne.

43. 160: methyl-19-nor-A -5a-pregnene 170:,21-

diol-2,20-dione.

44. 60c methyl 19 nor-A -5a-pregnene-17a,-

21-diol-2,2(}-dio'ne'.

Example VII A mixture of 1 g. of 60,16a-dimethyl-19-nor-A-5apregnene-17oa21-dio1-2,20-dione (Cpd. No. 39), '8 cc. of pyridine and4 cc. of acetic anhydride waskept at room temperature overnight, pouredinto iced water, the formed precipitate filtered, washed with water anddried. Crystallization from acetone-hexane produced the 21-acetate of6a,16a dimethyl 19 nor A 5a-pregncne-17a,21- diol-2,20-dione (Cpd. No.45

The compounds Nos. 40 to 44, inclusive, were treated following the sameprocedure, to give respectively:

Cpd. No.:

46. 21 acetate of 6a,16fi-dimethy1-19-nor-A -5apregnene-l7a,21-diol-3,20-dione.

47. 21-acetate of 16p-methyl-19-nor-A-5a-pregnene-1'7a,2l-diol-2,20-dione.

48. 21-acetate of -19-nor-A -5a-pregnene-17u,21-

diol-2,'20-dione 49. ZI-acetate of 16a-methyl-19-nor-A-5a-pregnone-1170421-diol-2,20-dione.

50. ZI-acetate of 6a-methyl-l9-nor-A-5u-pregnene-l7a,21-diol-2,20-dione.

Example VIII The compounds Nos. 39 to 44, inclusive, were treatedaccording to Example VII, except that acetic anhydride was substitutedby propionic anhydride, caproic anhydride and cyclopentylpropionicanhydride, to obtain the corresponding C-21-propionates, C-Zd-caproatesand C-21- cyclopentylpropionates of the aforesaid compounds.

Example IX To a solution of 5 g. of the ZI-acetate of 6a,16u-dimethyll9-nor-A -5a-pregnene-17u,21-diol-2,20 dione (Cpd. No. 45) in 100 cc. ofanhydrous benzene, there were added 1 g. of p-toluenesulfonic acid and10 cc. of acetic anhydride and the mixture was allowed to stand for 24hours at room temperature, poured into ice and water, and the resultingmixture stirred to etfect hydrolysis of the excess anhydride. Thebenzene layer was separated and washed with 10% sodium carbonatesolution and water. Drying, evaporation and crystallization of theresidue from ether-hexane produced the diacetate of 60:; 16adimethyl-19-nor-A -5apregnene-17a,21-diol-3,2O- dione (Cpd. No. 51).

Upon applying the same technique to the compounds Nos. 46 to 50,inclusive, there were obtained the corresponding diesters which are setforth below:

Cpd. No.:

52. Diacetate of 6a,16,6-dimethyl-19-nor-A-5apregnene-17a,21-diol-3,20-dione.

ll) Cpd. No.:

53. Diacetate of l6,8-rnethyl-19-nor-A-5a-pregnene-17a,21-diol-3,20-dione.

54. Diacetate of 19-nor-A -5rx-pregnene-17a,21-

diol-3,20-dione.

55. Diacetate of 16a-methyl-19-nor-A-5a-pregnene-l7a,21-diol-3,20-dione.

S6. Diacetate of 6a-methyl-19-nor-Al-5a-pregnene-17a,21-diol-3,20-dione.

Example X The compounds Nos. 45 to 50, inclusive, were treated followingthe procedure of Example IX, except that acetic anhydride wassubstituted by propionic anhydride, caproic anhydride, andcyclopentylpropionic anhydride, to give the corresponding2l-acetate-l7-propionates, 21-acetate-l7- caproates and21=acetate-17-cyclopentylpropionates of the aforementioned compounds,

The C-21 esters obtained in Example VIII were treated in the samemanner, to obtain the respective C-17, C-21 steroid diesters.

Example XI The following solutions A, B and C were prepared usingdistilled water as solvent: solution A was prepared by mixing 425 cc. ofa 1.742% dipotassic phosphate solution (Ki-IP0 with 75 cc. of 1.38%monosodic phosphate; solution B was prepared by diluting a mixture of 1lt. of 4.5% sodium chloride solution, 40 cc. of a 5.75% potassiumchloride solution and 10 cc. of a 19.1% magnesium sulfiate, to a volumeof 5 lt.; solution C was prepared by dissolving 20.9 g. of furnaric acidand 14.4 g. of sodium hydroxide in 1 lt. of water and diluting thesolution to 1.2 lt. Then 475 cc. of solution A, 4.32 lt. of solution Band 1.2 It. of solution C were mixed.

Adrenal glands of recently slaughtered cattle, defatted, were ground ina meat grinder until a homogeneous mass was obtained; to 1 kg. ofhomo-genate was added 2 liters of the mixture of A, B, and C solutionswith vigorous stirring. To the mixture there was then added 1 g. of theZI-acetate of 6a,16a-dimethyl-19-norA -5a-pregnen-17a,21-di0l-2,20-dione (Cpd. No. 45) dissolved in 5.35 parts ofpropyleneg-lycol, the mixture was stirred at 28- 37 C. for 3 hours, 13liters of acetone were added and the mass was stirred at roomtemperature for an additional 1 hour.

The acetone extract was separated by filtration, the ground adrenalswere washed with 6 liters of acetone, the extracts were combined and thesolvent removed by distillation under reduced pressure. Chromatographyon alumina and crystallization of the solid fractions eluted withbenzene-ether (70:30) afforded the 21-acetate of 6a,16adimethyl 19 nor A-5a-pregnene-11 8,17u,21-triol- 2,20-dione (Cpd. No. 57).

The compounds Nos. 46 to 50, inclusive, were treated following the sameprocedure, thus producing respectively:

Cpd. No:

58. 21-acetate of 6a,16(3-dimethyl-19-nor-A-5apregnene-l1,8,17a,21-triol-2,20-dione.

59. 21-acetate of 16,8-methyl-19-nor-A -5o -pregnene-l1,8,17a,2l-triol3,20 dione.

60. 21-acetate of 19-nor-A -5a-pregnene-1 118,1711,

21-triol-3,20-dione.

61. 21-acetate of 16a-methyl-19-nor-A Q-Sapregnene-l113,17a,21-triol-3,20-dione.

62. ZI-acetate of 6a-methyl-19-nor-A-Sa-pregnene-l1p,17a,21-triol-3,20-dione.

Example XII The steroidal C-21-propionates, C-21-caproates andC-2l-cyclopentylpropionates obtained in Example VIII were treatedfollowing the hydroxylation procedure of Example XI, to give thecorresponding C-ll hydroxy steroid derivatives.

1 1 Example XIII The compounds Nos. 57 to 62, inclusive, were reacted ina manner according to Example IV, thus giving respectively:

Cpd. No.:

63. 21-acetate of 6a,l6a-dimethyl-l9-nor-A -5a.-

pregnene-17a,21-diol-2,11,20-trione.

64. 21 acetate of 6m,l6fi-dimethyl-19-nor-A-5mpregnene-17ot,2l-diol-2,11,20-trione.

65. 21 acetate of l6B-methyll9-nor-A-5ot-pregnene-17a,21-diol-2,11,20-trione.

66. 21-acetate of 19-nor-A -5a-pregnene-17a,21-

diol-2,1 1,20-trione.

67. 21-acetate of 16a-methyl-l9-nor-A-5a-pregnene-17a,21-diol-2,11,20-trione.

68. 21-acetate of 6a-methyl-19-nor-A -5m-pregnene-17 oz,21-dll-2,l1,20-trione.

Example XIV The C-ll hydroxy steroid C-ZI-propionates, C-21-caproatesand C-2l-cyclopentylpropionates (obtained according to Example XII) wereoxidized in an identical manner, by following the technique of ExampleIV, to obtain the corresponding C-21-aeyloxy-17-keto steroidderivatives.

Example XV A solution of g. of 6a,16u-dimethyl-19-nor-A-5upregnene-17a,21-diol-2,20-dione (Cpd. No. 39) in 25 cc. of pyridinewas cooled to 0 C. Under stirring, there was added 1.3 g. of tosylchloride, the mixture was kept for 16 hours at 0 C., diluted with 100cc. of chloroform, washed with dilute hydrochloric acid, water, aqueoussodium bicarbonate solution and again with water, dried over anhydroussodium sulfate and then evaporated to dryness under reduced pressure.Thus, there was obtained the crude 21-tosylate of6u,l6a-dimethyl-l9-nor- A -5a-pregnene-17a,2l-diol-2,2O-dione.

A solution of 2.5 g. of the above crude compound in 100 cc. of glacialacetic acid was treated with 7 g. of sodium iodide and the mixture wasrefluxed for 2 hours, poured into ice water and extracted several timeswith methylene chloride; the extracts were combined, washed successivelywith aqueous sodium carbonate solution, sodium sulfite solution andwater and then evaporated. By crystallization of the residue fromacetone-hexane, there was obtained 6a,16m-dimethyl-19-nor-A -5o-pregnen-17o:-Ol-2,20-di0116 (Cpd. No. 69).

The compounds Nos. 40 to 44, inclusive, were treated following the twopreceding procedures to produce the respective final compounds Which areenumerated below:

Cpd. No.:

70. 6a,16fl-dimethy1-19-nor-A -5oc-pregnen-17a-ol- 2,20-dioue.

71. 16fl-rnethyl-l9-nor-A -5 a-pregnen-l7 a-ol-2,

ZO-dione.

72. 19-nor-A Jot-pregnan-l7u-ol-2,2O-dione.

73. 16e-methyl-19-nor-A -Sa-pregnen-1701-01-2,

ZO-dione.

74. Got-methyl-19-nor-A -5a-pregnen-17ot-ol-2,20-

dione.

Example XVI The compounds Nos. 69 to 74, inclusive, were treatedfollowing the same technique as in Example 1X, to give respectively:

Cpd. No.:

75. Acetate of 6a,l6a-dimethyl-19-nor-A -5apregnen-17a-ol-2,20-dione.76. Acetate of 6a,16B-dimethyl-19-nor-A -5apregnen-l7e-ol-2,20-dione.77. Acetate of lGB-methyl-19-nor-A -5rx-pregnen- 17oc-OlZ,ZU-(ll0l'l6.

Cpd. No.: a

78. Acetate of 19-nor-A -5u-pregnen-17a-ol-2,20-

dione.

79. Acetate of 16a-methyl-19-nor-A -Sa-pregnen- 17a0l2,20-di0116.

80. Acetate of Got-methyl-19-nor-A -5a-pregnen- 17aOl-2,20-d'i011.

Example XVII The starting compounds of the preceding example weretreated by the procedure described in the same example, except thatacetic anhydride was substituted by propionic anhydride, caproicanhydride and cyclopentylpropionic anhydride, to give the correspondingsteroidal C-17-propionates, C-17-caproates and C17-cyclopentylpropiomates of the aforesaid compounds.

Example XVIII 2 g. of compound No. 57 were dissolved in 50 cc. ofmethanol and treated with 5 cc. of a 4% aqueous solution of potassiumhydroxide; the reaction mixture was stirred for 1 hour under anatmosphere of nitrogen at 0 C.; the mixture was neutralized with aceticacid and the methanol distilled under reduced pressure. The residue wastriturated with water and the solid collected, washed with water, driedand recrystallized from ethyl acetate-methanol, thus producing6a,1Get-dimethyl-19-nor-A -5apregnene-llfl,17a,21-triol-2,20-dione (Cpd.No. 81).

The compounds Nos. 58 to 68, inclusive, were treated by the sameprocedure to produce the corresponding 21- free alcohols.

I claim:

1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is amember of the group consisting of hydrogen, rat-methyl and fl-methyl;and R is selected from the group consisting of hydrogen and methyl.

2. 611,16 dimethyl l9 nor A) 50c pregnen- 17a-ol-2,20'-dione.

3. 60;,165 dimethyl l9 nor A100) 5a pregnen- 17a-ol-2,20-dione.

4. methyl 19 nor A 50c pregnen col-2,20-dione.

5. 16a methyl 19 nor A 50c pregnen 17a.- ol-2,20-dione.

6. 60a methyl 19 nor A 50c pregnen 17aol-2,20-dione.

7. A compound of the following formula:

wherein R and R are selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is amember of the group Consisting of hydrogen, a-methyl and fi-methyl, R isselected from the group consisting of hydrogen and methyl; and X isselected from the group consisting of hydrogen, a keto group and afi-hydroxyl group.

9. 21-acetate of 16,8-methyl-19-nor-A -Sa-pregmnell ,8, 170:,21-triol-2,20-dione.

10. ZI-acetate of 19-nor-A -Sa-preghehe-l13,17, 21-trio1-2,20-dione.

11. 21 acetate of 160: methyl 19 nor A -5apregnenel15,1704)1-triol-2,20-di0ne.

12. 21 acetate of 6a methyl 19 nor A100)5apregnene-l1p,17a,21-triol-2,20-dione.

13. 21 acetate of 6a,l6vt dimethyl l9 nor ASa-pregnene-l113,17a,21-triol-2,20-di0ne.

14. 6a,16u dimethyl 19 nor A c pregnene-l 1,6, 17a,21-t1iO1-2,20-di0n.

15. 21 acetate of 611,16 dirnethyl 19 nor ASa-pregnene-17a,21-diol-2,11,20-trione.

16. 21 acetate of 6a,16p dimethyl 19 nor A5a-pregnene-17a,21-diol-2,11-20-trione.

17. 21 acetate of 16,8 methyl 19 nor A-5apregnene-17a,21-dio1-2,11,20-trione.

18. 21 acetate of 19 nor A100) 5a pregnene- 17a,21-diol-2,1 1,20-trione.

19. 21 acetate of 16a methyl 19 nor A50cpregnene-17a,21-diol-2,11,20-trione.

20. 21 acetate of 6a methyl 19 nor A5apregnene-17a,21-diol-2,11,20-trione.

No references cited.

1. A COMPOUND OF THE FOLLOWING FORMULA:
 7. A COMPOUND OF THE FOLLOWINGFORMULA: